Our goal is to improve understanding of the mechanisms for cardiac arrhythmias, the ways in which these mechanisms can be precisely identified and the mechanisms of action of antiarrhythmic drugs to permit more accurate diagnosis and more effective treatment. We have selected this area because cardiac arrhythmias such as vent- ricular tachycardia and fibrillation are the major cause of death in individuals with coronary artery disease or heart failure. Our specific aims are to determine the mechanisms by which ischemia and infarction bring about alterations in the electrical activity of cardiac cells that lead to reentrant rhythms, how both the functional and structural properties of the circus path influence reentrant rhythms and their responses to drugs and which actions of antiarrhythmic drugs are necessary for prevention and termina- tion of reentrant excitation. We will attempt to answer these questions by closely integrated studies examining the effects of ischemic factors and antiarrhythmic drugs on single channel currents studied with patch-clamp methods in single myocytes or whole-cell currents studied with voltage-clamp and intracellular dialysis in both normal myocardial and Purkinje cells and those modified by acute and subacute infarction, by studies using ion selective microelectrodes to measure alterations in intracellular and extracellular composition caused by factors designed to mimic ischemia, by studies with microelectrodes on normal cardiac tissues and tissues damaged by ischemia and by studies on reentrant arrhythmias and drug actions in canine models of reentrant arrhythmias. These models include two types of reentrant atrial arrhythmias and also ventricular tachycardia in the infarcted heart. Finally, we will use a new optical recording method to study ventricular tachycardia and ventricular fibrillation and determine how electrical shocks terminate reentry and fibrillatory rhythms.